As part of a project investigating the possible role of the insulin receptor tyrosine kinase in the pathogenesis of insulin resistance in Pima Indians, the kinase activity was determined in muscle biopsies obtained after feeding subjects each of a "traditional" high carbohydrate, Pima-type diet, and a "modern", high-fat Western-style diet. The modern diet induced insulin resistance and increased the kinase activity in the majority of subjects. The change in kinase activity were negatively correlated with the changes in insulin action and positively correlated with the changes in plasma insulin levels. When the time-course of the in vivo kinase stimulation was studied, kinase activation was rapid and detectable in less than 10 minutes of insulin infusion. Receptors previously exposed to insulin in vivo displayed a higher kinase activity in vitro, indicating that circulating insulin primes in active receptor molecules for subsequent kinase activation. It is possible that the kinase increases with plasma insulin levels as part of a mechanism compensating for insulin resistance at a distal site.